Abstract:Glycogen is a polymer of α-1,4- and α-1,6-linked glucose units that provides a readily available source of energy in living organisms. Glycogen synthase (GS) and glycogen phosphorylase (GP) are the two enzymes that control, respectively, the synthesis and degradation of this polysaccharide and constitute adequate pharmacological targets to modulate cellular glycogen levels, by means of inhibition of their catalytic activity. Here we report on the synthesis and biological evaluation of a selective inhibitor tha… Show more
“…1, was tested against purified preparations of commercially available RMGP a and recombinantly produced Ec GS and SuSy4. 16 First, to establish the optimal conditions of the assay, the kinetic parameters K m and V max of the three enzymes for their respective substrates were determined: RMGP a activity was measured in the direction of glycogen phosphorolysis and Ec GS and SuSy4 in the direction of synthesis of glycogen and sucrose, respectively (Fig. S-1 and Table S-2, ESI † ).…”
Section: Resultsmentioning
confidence: 99%
“…12 The synthesis of molecules with new inhibitory profiles in terms of potency and/or selectivity is of special interest in the case of GTs, since there are few known inhibitors. 13–16 …”
Glycogen synthase (GS) and glycogen phosphorylase (GP) are the key enzymes that control, respectively, the synthesis and degradation of glycogen, a multi-branched glucose polymer that serves as a form of energy storage in bacteria, fungi and animals. An abnormal glycogen metabolism is associated with several human diseases. Thus, GS and GP constitute adequate pharmacological targets to modulate cellular glycogen levels by means of their selective inhibition. The compound 1,4-dideoxy-1,4-imino-D-arabi-nitol (DAB) is a known potent inhibitor of GP. We studied the inhibitory effect of DAB, its enantiomer LAB, and 29 DAB derivatives on the activity of rat muscle glycogen phosphorylase (RMGP) and E. coli glycogen synthase (EcGS). The isoform 4 of sucrose synthase (SuSy4) from Solanum tuberosum L. was also included in the study for comparative purposes. Although these three enzymes possess highly conserved catalytic site architectures, the DAB derivatives analysed showed extremely diverse inhibitory potential. Subtle changes in the positions of crucial residues in their active sites are sufficient to discriminate among the structural differences of the tested inhibitors. For the two Leloir-type enzymes, EcGS and SuSy4, which use sugar nucleotides as donors, the inhibitory potency of the compounds analysed was synergistically enhanced by more than three orders of magnitude in the presence of ADP and UDP, respectively. Our results are consistent with a model in which these compounds bind to the subsite in the active centre of the enzymes that is normally occupied by the glucosyl residue which is transferred between donor and acceptor substrates. The ability to selectively inhibit the catalytic activity of the key enzymes of the glycogen metabolism may represent a new approach for the treatment of disorders of the glycogen metabolism.
“…1, was tested against purified preparations of commercially available RMGP a and recombinantly produced Ec GS and SuSy4. 16 First, to establish the optimal conditions of the assay, the kinetic parameters K m and V max of the three enzymes for their respective substrates were determined: RMGP a activity was measured in the direction of glycogen phosphorolysis and Ec GS and SuSy4 in the direction of synthesis of glycogen and sucrose, respectively (Fig. S-1 and Table S-2, ESI † ).…”
Section: Resultsmentioning
confidence: 99%
“…12 The synthesis of molecules with new inhibitory profiles in terms of potency and/or selectivity is of special interest in the case of GTs, since there are few known inhibitors. 13–16 …”
Glycogen synthase (GS) and glycogen phosphorylase (GP) are the key enzymes that control, respectively, the synthesis and degradation of glycogen, a multi-branched glucose polymer that serves as a form of energy storage in bacteria, fungi and animals. An abnormal glycogen metabolism is associated with several human diseases. Thus, GS and GP constitute adequate pharmacological targets to modulate cellular glycogen levels by means of their selective inhibition. The compound 1,4-dideoxy-1,4-imino-D-arabi-nitol (DAB) is a known potent inhibitor of GP. We studied the inhibitory effect of DAB, its enantiomer LAB, and 29 DAB derivatives on the activity of rat muscle glycogen phosphorylase (RMGP) and E. coli glycogen synthase (EcGS). The isoform 4 of sucrose synthase (SuSy4) from Solanum tuberosum L. was also included in the study for comparative purposes. Although these three enzymes possess highly conserved catalytic site architectures, the DAB derivatives analysed showed extremely diverse inhibitory potential. Subtle changes in the positions of crucial residues in their active sites are sufficient to discriminate among the structural differences of the tested inhibitors. For the two Leloir-type enzymes, EcGS and SuSy4, which use sugar nucleotides as donors, the inhibitory potency of the compounds analysed was synergistically enhanced by more than three orders of magnitude in the presence of ADP and UDP, respectively. Our results are consistent with a model in which these compounds bind to the subsite in the active centre of the enzymes that is normally occupied by the glucosyl residue which is transferred between donor and acceptor substrates. The ability to selectively inhibit the catalytic activity of the key enzymes of the glycogen metabolism may represent a new approach for the treatment of disorders of the glycogen metabolism.
“…In 2015, Diaz-Lobo et al [ 21 ] reported on the synthesis and biological evaluation of O -glycoside—a selective inhibitor that consists of an azobenzene moiety glycosidically linked to the anomeric carbon of a glucose molecule. The molecule incorporates an azobenzene photoswitch whose conformation can be significantly altered by irradiation with UV light.…”
Section: O
-Glycosides As Antidiabetic Agentsmentioning
confidence: 99%
“…Although compound 9 was synthesized as a 1:4 mixture of the α- and β-anomers, analysis suggested that the more abundant β-anomer is the one responsible for the observed inhibition. So, Diaz-Lobo et al showed that the ability to selectively photocontrol the catalytic activity of key enzymes of glycogen metabolism might represent a new approach for the treatment of glycogen metabolism disorders [ 21 ]. Scheme 1 Synthesis of 4-(phenylazo)phenyl- d -glucopyranoside 9 [ 21 ] …”
Section: O
-Glycosides As Antidiabetic Agentsmentioning
This review is an effort to summarize recent developments in synthesis of
O
-glycosides and
N
-,
C
-glycosyl molecules with promising antidiabetic potential. Articles published after 2000 are included. First, the
O
-glycosides used in the treatment of diabetes are presented, followed by the
N
-glycosides and finally the
C
-glycosides constituting the largest group of antidiabetic drugs are described. Within each group of glycosides, we presented how the structure of compounds representing potential drugs changes and when discussing chemical compounds of a similar structure, achievements are presented in the chronological order.
C
-Glycosyl compounds mimicking
O
-glycosides structure, exhibit the best features in terms of pharmacodynamics and pharmacokinetics. Therefore, the largest part of the article is concerned with the description of the synthesis and biological studies of various
C
-glycosides. Also
N
-glycosides such as
N
-(β-
d
-glucopyranosyl)-amides,
N
-(β-
d
-glucopyranosyl)-ureas, and 1,2,3-triazolyl derivatives belong to the most potent classes of antidiabetic agents. In order to indicate which of the compounds presented in the given sections have the best inhibitory properties, a list of the best inhibitors is presented at the end of each section. In summary, the best inhibitors were selected from each of the summarizing figures and the results of the ranking were placed. In this way, the reader can learn about the structure of the compounds having the best antidiabetic activity. The compounds, whose synthesis was described in the article but did not appear on the figures presenting the structures of the most active inhibitors, did not show proper activity as inhibitors. Thus, the article also presents studies that have not yielded the desired results and show directions of research that should not be followed. In order to show the directions of the latest research, articles from 2018 to 2019 are described in a separate Sect.
5
. In Sect.
6
, biological mechanisms of action of the glycosides and patents of marketed drugs are described.
“…Photochromism has attracted increasing interest of carbohydrate community to develop photoswitchable glycoconjugates for light‐controlled carbohydrate‐lectin interactions, intracellular target recognition, cell adhesion, chiral discrimination, photoregulation of enzyme activity and protein conformation, or as photoresponsive surfactants, hydrogelators, organogelators, liquid crystals, as well as water‐compatible molecular logic gate. Azobenzene,, spiropyran, and diarylethene have been used as photochromic moiety in these glycoconjugates, with the azobenzene being the most employed one, probably due to its small size, its excellent photostability and the large changes in molecular size, conformation and dipole moment between E and Z isomers.…”
Reversible photocontrol of glycosides and glycoconjugates structures is a very attractive approach to modulate, in a spatiotemporal way, the various properties and biological activities of carbohydrates. We have synthesized three new azobenzene‐derived glycomacrolactones from thioglycopyranosides. The synthesized cyclic glycoazobenzenes can be reversibly photoisomerized between E and Z isomers with high fatigue resistance. A 1H NMR spectroscopic study shows that E → Z isomerization of glycomacrocycles induces large conformational change of the macrocyclic structures, without changing sugar 4C1 chair conformation. The Z‐glycoazobenzenes can be thermally converted back to the E‐isomers. Interestingly, these 16 to 17‐membered Z‐glycomacrolactones display higher thermal stability than the reported macrocyclic azobenzenes, the half‐life varying from 37 to 72 days. The excellent photoswitching property and bistability of the synthesized glycoazobenzenes open a new opportunity for the convergent synthesis of diastereomers of glycomacrocycles. Furthermore, chiroptical properties have been observed for both E and Z glycomacrolactones. The geometry of different isomers of macrocycles has been optimized with DFT calculations. Theoretical CD spectra obtained by TD‐DFT suggest that the E and Z glycomacrocycles adopt preferentially (P) helical structure for the azobenzene moiety.
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